Solidification of nanosuspensions for the production of solid oral dosage forms and inhalable dry powders

Abstract

Introduction: Nanosuspensions combine the advantages of nanotherapeutics (e.g. increased dissolution rate and saturation solubility) with ease of commercialisation. Transformation of nanosuspensions to solid oral and inhalable dosage forms minimises the physical instability associated with their liquid state, enhances patient compliance and enables targeted oral and pulmonary drug delivery.

Areas covered: This review outlines solidification methods for nanosuspensions. It includes spray and freeze drying as the most widely used techniques. Fluidised-bed coating, granulation and pelletisation are also discussed as they yield nanocrystalline formulations with more straightforward downstream processing to tablets or capsules. Spray-freeze drying, aerosol flow reactor and printing of nanosuspensions are also presented as promising alternative solidification techniques. Results regarding the solid state, in vitro dissolution and/or aerosolisation efficiency of the nanocrystalline formulations are given and combined with available in vivo data. Focus is placed on the redispersibility of the solid nanocrystalline formulations, which is a prerequisite for their clinical application.

Expert opinion: A few solidified nanocrystalline products are already on the market and many more are in development. Oral and inhalable nanoparticle formulations are expected to have great potential especially in the areas of personalised medicine and delivery of high drug doses (e.g. antibiotics) to the lungs, respectively.

Keywords:

• dry powder for inhalation
• matrix former
• nanosuspension
• redispersibility
• solidification
• solid oral dosage forms

Article highlights

• Nanosuspensions are submicron dispersions of nanosized drug particles stabilized by surfactants, polymers, or a mixture of both.

• The main advantages of nanosuspensions are increased dissolution and saturation solubility, enhanced chemical stability, and rapid commercialization.

• Transformation of nanosuspensions to the solid state ensures their long-term stability and increases patient compliance.

• Various drying techniques, with some of them well established (e.g. spray drying) while others are less applied in pharmaceutical technology (e.g. aerosol flow reactor) have been used for the transformation of nanosuspensions to solid oral dosage forms and dry powders for inhalation.

• Transformation of nanosuspensions to micron-sized nanoparticle agglomerates is a way to deliver higher doses to the lungs compared to the conventional adhesive mixtures approach using dry powder inhaler (DPI) formulations.

• Formulation and solidification process parameters influence the redispersibility (reformation of nanoparticles upon rehydration), which is a prerequisite for their superior clinical performance. Addition of matrix formers is a common strategy in order to achieve redispersible solidified nanosuspensions.

This box summarizes key points contained in the article.

Declaration of Interest

M Malamatari is supported by a PhD scholarship from the Center of Doctoral Training in Targeted Therapeutics and Formulation Science (EPSRC grant: EP/I01375X/1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

^1. Recently, there is an increasing concern regarding nanotoxicology mainly due to the ability of nanoparticles to enter cells. The toxicity of nanoparticles is related to their cellular uptake and intracellular fate. According to the nanotoxicological classification system proposed by Müller et al. [21], nanocrystals are in the low/non-risk group. Their typical size (100 nm < d < 1000 nm) does not allow cell endocytosis, and their biodegradable nature is associated with low danger of biopersistency. However, studies should be conducted on the interaction of nanocrystals with cells and their cellular uptake has to be considered when developing nanocrystalline-based products [21].

^2. Regarding pulmonary drug delivery, drug absorption and local bioavailability depend upon the fraction of deposited drug that dissolves in the lungs. Mucociliary clearance and absorption are two competing mechanisms, and this can lead to bioavailability reduction for drug particles with low dissolution velocity [97]. Nanoparticle-based formulations have been found to promote more rapid absorption following inhalation of poorly water-soluble drug that have dissolution-limited drug absorption (e.g. fluticasone propionate, beclomethasone dipropionate, budesonide, itraconazole, fentanyl).[98]